Alzheimer's disease (AD) is the most prevalent form of all neurodegenerative disorders. Approximately 100,000 victims die and 360,000 new cases of Alzheimer's disease are diagnosed each year. To date, there is no effective treatment for Alzheimer's disease. Research has suggested a number of possible approaches to treatment, such as Cholinergic strategies: Acetylcholinesterase inhibitors (e.g., Tacrine®, Cognex®, or Exelon®) and MI muscarinic receptor agonists; Neurotrophic factors (e.g., Nerve growth factor); Inhibitors of oxidation (e.g., vitamin E); Metal chelating agents; Immunotropic drugs; Non-narcotic analgesics (e.g., Ibuprofen); Inhibitors of beta-A4 aggregation; Estrogen, etc. But so far, none of these approaches has been clearly demonstrated to cause a significant improvement in the majority of patients afflicted with Alzheimer's disease. Thus, a long felt and high medical need exists for new drugs with a novel mode of action for the treatment of Alzheimer's Disease.
The precise mechanisms leading to AD are not completely understood, but since the isolation of the E4 isoform of ApoE as the most significant risk factor of AD (Strittmatter, W. J. et al., 1993), a mechanistic link has been established between cholesterol metabolism and the formation of amyloid plaques. In humans, high level of cholesterol at mid-age is associated with a higher risk of AD (Kivipelto, M. et al, 2002) and cholesterol concentrations are increased in AD brains (Cutler, R. G. et al., 2004). ApoE which binds cholesterol and could regulate lipid transport into neurons is found in senile plaques (Namba, Y. et al., 1991), along with cholesterol itself (Mori, T. et al., 2001). In Niemann-Pick disease type C, due to a mutation of the gene NPC1 that encodes a protein implicated in intracellular transport of cholesterol to post-lysosomal destinations, cholesterol accumulates in neurons together with Aβ peptide in late endosomes (Jin, L. W. et al., 2004). In mouse model of AD, dietary cholesterol accelerates Aβ deposition whereas cholesterol-lowering drugs lower it (Refolo, L. M. et al., 2001). Inhibition of acyl-coenzyme A cholesterol acyltransferase (ACAT), an enzyme that controls the equilibrium between free cholesterol and cholesteryl esters was shown to reduce amyloid pathology (Hutter-Paier, B. et al., 2004). However, inactivation of genes involved in the transport of cholesterol (ApoE, ABCA1 and LDL receptor) in various transgenic AD mice has led to divergent results, likely because changes in cholesterol metabolism were also induced during development, causing uncontrollable compensatory mechanisms. In vitro, changes in the cholesterol content of the membrane induces parallel changes in Aβ secretion (Simons, M. et al, 1998, Ehehalt, R., et al., 2003). It is believed that this modulation occurs at the levels of lipid rafts. A high cholesterol content could facilitate the clustering of β secretase embedded in rafts with APP (Ehehalt, R., et al., 2003); translocation of the γ-secretase complex to the raft could have a similar consequence (Vetrivel, K. S. et al., 2005). On the other hand, there is a negative feedback mechanism between APP processing and neuronal lipid metabolism since Aβ40 inhibits HMG-CoA reductase activity and thus cholesterol synthesis (Grimm, M. O. et al., 2005).
International patent application WO2004/055201 describes cholesterol 24-hydroxylase as a therapeutic target for the treatment of Alzheimer's disease.
The cholesterol 24-hydroxylase is a neuronal enzyme that is coded by the CYP46A1 gene. It converts cholesterol into 24-hydroxycholesterol and has a critical role in the efflux of cholesterol from the brain (Dietschy, J. M. et al., 2004). Brain cholesterol is essentially produced—but cannot be degraded—in situ, and intact blood-brain barrier restricts direct transportation of cholesterol from the brain (Dietschy, J. M. et al., 2004). 24-hydroxycholesterol is able to cross the plasma membrane and the blood-brain barrier and reaches the liver where it is degraded. During the early stages of AD, 24-hydroxycholesterol concentrations are high in CSF and in peripheral circulation. In later stages of AD, concentrations of 24-hydroxycholesterol may fall likely reflecting neuronal loss (Kolsch, H. et al., 2004). CYP46A1 is expressed around the amyloid core of the neuritic plaques in the brain of AD patients (Brown, J., 3rd et al., 2004).